The major goal of this project has been to identify the mechanisms by which such adoptive chemoimmunotherapy (ACIT) results in tumor destruction. By using B6 strain tumor-bearing hosts and immune congenic B6/Thy 1.1 donors (i.e., express different Thy determinants), it has been possible to distinguish host T cells from donor T cells and to analyze the relative contribution of each to tumor eradication. Donor T cells have been demonstrated to persist for more than 100 days following adoptive transfer and to contain the tumor-reactive T-cell population present in the host. Moreover, depletion of T cells in vivo as late as 35 days after adoptive transfer by infusion of monoclonal antibodies to Thy antigens has resulted in tumor recurrences. Thus, host tumor immunity does not appear to contribute to tumor eradication, and the donor T cells responsible for this therapeutic effect must persist for greater than 35 days to be fully effective. The effector cells potentially operative in vivo are being examined. Adoptive transfer of noncytolytic Lyt 1+2- T cells into tumor-bearing T-deficient hosts resulted in complete tumor eradication. Analysis of the T-cell compartment present in such cured mice confirmed the presence of only donor Lyt 1+2- T cells, which were not cytolytic but were capable of making lymphokinein response to tumor. Thus, tumor lysis must be mediated by mononuclear cells activated by these lymphocytes. Studies are being performed to identify this effector cell and the nature of the activation factor secreted by immune T cells. Ongoing studies are also examining the potential role of adoptively transferred purified Lyt 1-2+ T cells. Such cells can mediate a limited antitumor effect if infused after being rendered cytolytically active by in vitro culture with tumor cells. The therapeutic activity appears to be markedly augmented by concurrent in vivo administration of purified IL-2, a T-cell growth factor normally produced by helper T cells. Thus, cytolytic T cells can function in vivo against established tumor, but require either helper T cells or helper factors for optimal activity. Studies are now being performed to assess the nature of the tumor antigen recognized by helper and cytotoxic T cells and the role of helper T-cell products in augmenting CTL activity (IT).